Obesity and Lipid Metabolism Disorders--Body Fat Loss
In humans obesity can be defined as a body weight exceeding 20% of the desirable body weight for individuals of the same sex, height and frame (Salans, L. B., in Endocrinology & Metabolism, 2d Ed., McGraw-Hill, New York 1987, pp. 1203-1244; see also, R. H. Williams, Textbook of Endocrinology, 1974, pp. 904-916). In other animals (or also in humans) obesity can be determined by body weight patterns correlated with prolactin profiles given that members of a species that are young, lean and "healthy" (i.e., free of any disorders, not just metabolic disorders) have daily plasma prolactin level profiles that follow a regular pattern that is highly reproducible with a small standard deviation.
Obesity, or excess fat deposits, correlate with and may trigger the onset of various lipid metabolism disorders, e.g. hypertension, Type II diabetes, atherosclerosis, etc.
Even in the absence of clinical obesity (according to the above definition) the reduction of body fat stores (notably visceral fat stores) in man especially on a long-term or permanent basis would be of significant benefit, both cosmetically and physiologically.
The reduction of body fat stores in domestic animals (as well as pets) especially on a long-term or permanent basis would also obviously be of considerable economic benefit to man, particularly since farm animals supply a major portion of man's diet; and the animal fat may end up as de novo fat deposits in man.
Whereas controlled diet and exercise can produce modest results in the reduction of body fat deposits, prior to the cumulative work of the present inventors (including the prior co-pending patent applications and issued U.S. patents referred to below), no truly effective or practical treatment had been found for controlling obesity or other lipid metabolism disorders.
Hyperlipoproteinemia is a condition in which the concentration of one or more of cholesterol- or triglyceride-carrying lipoproteins (such as chylomicrons, very low density lipoproteins or VLDL and low-density lipoproteins or LDL) in plasma exceeds a normal limit. This upper limit is generally defined as the ninety-fifth percentile of a random population. Elevated levels of these substances have also been positively correlated with atherosclerosis and the often resulting cardiac infarction, or "heart attack", which accounts for approximately half of all deaths in the United States. Strong clinical evidence has been presented which correlates a reduction in plasma lipoprotein concentration with a reduced risk of atherosclerosis (Noma, A., et al., Atherosclerosis 49:1, 1983; Illingworth, D. and Conner, W., in Endocrinology & Metabolism, McGraw-Hill, New York 1987). Thus, a significant amount of research has been devoted to finding treatment methods which reduce levels of plasma cholesterol and triglycerides.
Another subset of the plasma lipoproteins found in vertebrates are high density lipoproteins, or HDL. HDL serve to remove free cholesterol from the plasma. A high HDL concentration as a percentage of total plasma cholesterol has been associated with a reduced risk of atherosclerosis and heart disease. Thus HDL are known in the lay press as "good" cholesterol. Therefore, therapeutic strategies involve attempts both to reduce plasma LDL and VLDL content (that is, reduce total plasma cholesterol), and to increase the HDL fraction of total plasma cholesterol. Several lines of research indicate that simply increasing HDL is of benefit even in the absence of LDL or VLDL reduction: Bell, G.P. et al., Atherosclerosis 36:47-54, 1980; Fears, R., Biochem. Pharmacol. 33:219-228, 1984; Thompson, G., Br. Heart J. 51:585-588, 1989; Blackburn, H. N.E.J.M. 309:426-428, 1983.
Current therapies for hyperlipoproteinemias include a low fat diet and elimination of aggravating factors such as sedentary lifestyle. If the hyperlipoproteinemia is secondary (i.e. incident to e.g. a deficiency of lipoprotein lipase or LDL receptor, various endocrine pathologies, alcoholism, renal disorders, hepatic disorders) then control of the underlying disease is also central to treatment. Hyperlipoproteinemias are also treated with drugs, which usually alter the levels of particular components of the total plasma cholesterol, as well as reduce the total plasma lipid component. Among the most recently introduced drugs to treat hyperlipoproteinemia is lovastatin (MEVACOR.RTM.) which selectively inhibits an enzyme involved in cholesterol production, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This drug specifically reduces total cholesterol and can cause a modest (5-10% increase in HDL concentrations. However, benefits from these therapies vary from subject to subject.
Moreover, use of the HMG-CoA enzyme inhibitor is sometimes accompanied by side effects such as liver toxicity, renal myoglobinuria, renal shutdown, and lenticular opacity. The risk of such side effects necessitates close monitoring of the patients (e.g., liver function is tested monthly).
Another drug prescribed against hyperlipoproteinemia is clofibrate. The effectiveness of clofibrate also varies from subject to subject and its use is often accompanied by such side effects as nephrotic syndromes, myalgia, nausea and abdominal pain.
Diabetes
Diabetes, one of the most insidious of the major diseases, can strike suddenly or lie undiagnosed for years while attacking the blood vessels and nerves. Diabetics, as a group, are far more often afflicted with blindness, heart disease, stroke, kidney disease, hearing loss, gangrene and impotence. One third of all visits to physicians are occasioned by this disease and its complications, and diabetes and its complications are a leading cause of untimely death in the United States and in the Western world.
Diabetes adversely affects the way the body uses sugars and starches which, during digestion, are converted into glucose. Insulin, a hormone produced by the pancreas, makes the glucose available to the body's cells for energy. In muscle, adipose (fat) and connective tissues, insulin facilitates the entry of glucose into the cells by an action on the cell membranes. The ingested glucose is normally converted in the liver to CO.sub.2 and H.sub.2 O (50%); to glycogen (5%); and to fat (30-40%), the latter being stored in fat depots. Fatty acids from the adipose tissues are circulated, returned to the liver for re-synthesis of triacylglycerol and metabolized to ketone bodies for utilization by the tissues. The fatty acids are also metabolized by other organs. Fat formation is a major pathway for carbohydrate utilization.
The net effect of insulin is to promote the storage and use of carbohydrates, protein and fat. Insulin deficiency is a common and serious pathologic condition in man. In insulin-dependent IDDM or Type I) diabetes the pancreas produces little or no insulin, and insulin must be injected daily for the survival of the diabetic. In noninsulin-dependent (NIDDM or Type II) diabetes the pancreas retains the ability to produce insulin and in fact may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, due to cellular resistance to insulin.
In either form of diabetes there are widespread abnormalities. In most NIDDM subjects, the fundamental defects to which the abnormalities can be traced are (1) a reduced entry of glucose into various "peripheral" tissues and (2) an increased liberation of glucose into the circulation from the liver. There is therefore an extracellular glucose excess and an intracellular glucose deficiency. There is also a decrease in the entry of amino acids into muscle and an increase in lipolysis. Hyperlipoproteinemia is also a complication of diabetes. The cumulative effect of these diabetes-associated abnormalities is severe blood vessel and nerve damage.
Other than the present invention and previous work by the present inventors (discussed below), no effective treatment has been found for controlling either hyperinsulinemia or insulin resistance. Hyperinsulinemia is a higher-than-normal level of insulin in the blood. Insulin resistance can be defined as a state in which a normal amount of insulin produces a subnormal biologic response. In insulin-treated patients with diabetes, insulin resistance is considered to be present whenever the therapeutic dose of insulin exceeds the secretory rate of insulin in normal persons. Insulin resistance is also associated with higher-than-normal levels of insulin i.e. hyperinsulinemia--when normal or elevated levels of blood glucose are present.
Previous Work of the Present Inventors
The present inventors and their co-workers have found that administration of certain prolactin inhibitors (e.g., dopamine agonists such as bromocriptine) and/or prolactin stimulators (e.g., dopamine antagonists, such as metoclopramide; serotonin agonists and precursors, such as 5-hydroxytryptophan) and particularly administration of such substances at predetermined times, reduce body fat stores, obesity, plasma triglycerides and cholesterol as well as hyperglycemia, hyperinsulinemia and insulin resistance: U.S. Pat. Nos. 4,659,715; 4,749,709; 4,783,469; 5,006,526 and PCT Application US92/11166.
Related Applications
Co-pending patent application Ser. No. 07/192,332 (now abandoned in favor of its Rule 62 continuation Ser. No. 999,685, abandoned in favor of application Ser. No. 08/287,066, now U.S. Pat. No. 5,496,803) discloses methods for regulating lipid metabolism disorders by administering prolactin (or both prolactin and a glucocorticosteroid ("GC")) into the bloodstream of an animal or human on a timed daily basis in an amount and for a period of time sufficient to modify and reset the neural phase oscillation of the prolactin daily rhythm. This modification was found to increase insulin sensitivity.
The prolactin (or prolactin and glucocorticosteroid) injections are timed to create a peak in the subject's daily prolactin (or both prolactin and glucocorticosteroid) profile that coincides in time with the peak prolactin level (or prolactin and GC peaks, respectively) of a lean, insulin-sensitive human in order to increase insulin sensitivity and reduce body fat stores. Injections of the same agent(s) are timed towards the peak prolactin level time of an obese subject to achieve fat gain in a lean subject, if desired.
Co-pending application Ser. No. 07/463,327 abandoned in favor of application Ser. No. 07/719,745, now U.S. Pat. No. 5,344,832, discloses a method of modifying and resetting the neural phase oscillations of both prolactin and GC in an obese animal by administering a dopamine agonist at a predetermined time of day such that the prolactin (and/or GC) peak(s) of the obese animal will be phase-shifted to coincide with those of a lean animal. This results in the reduction of at least one of body fat stores, body weight, hyperinsulinemia, hyperglycemia and/or the increase of insulin sensitivity.
Pirenzepine is not specifically disclosed in this or in the other applications discussed below. The property of pirenzepine of increasing HDL is also not disclosed.
In co-pending application Ser. No. 07/719,745, now U.S. Pat. No. 5,344,832, we have disclosed and claimed enhanced methods for modifying and resetting the phase as well as the amplitude of prolactin daily rhythms. These methods comprise both (a) administering to the subject a dopamine agonist just after the time at which the normal prolactin profile peaks to reduce prolactin levels to the low "day" levels and (b) administering to the subject a prolactin stimulator at a time before the prolactin level peaks in normal subjects to achieve or maintain a peak for prolactin at night-time. The objective of this treatment is alteration of the subject's prolactin level profile to mimic in shape and time the profile of a lean healthy human not suffering from one or more of these metabolic disorders.
Ser. No. 07/719,745, U.S. Pat. No. 5,344,832, also discloses and claims the further administration of a thyroid hormone to subjects that are being treated with a dopamine agonist and prolactin stimulator, especially to those subjects that are chronically or seasonally hypothyroid.
Co-pending application Ser. No. 07/995,292, now U.S. Pat. No. 5,585,347 discloses methods for determining whether the daily circulating prolactin profile in a subject is abnormal, and methods for normalizing prolactin profiles found to be aberrant. In pertinent part, the treatment method involves administration of a prolactin inhibitor no later than the time at which during waking hours prolactin level in the subject to be treated is at its highest, and may also involve administration of a prolactin stimulator timed to cause a peak of prolactin level to occur during night-time. The objective of this treatment is alteration ("sculpting") of the subject's prolactin profile to mimic in shape and time the profile of a lean healthy human not suffering from any disorders.
Work of Third Parties
As far as the present inventors know, administration of pirenzepine or methyl scopolamine or other muscarinic, especially M1, receptor antagonists has not been used to combat obesity or atherosclerosis or hyperlipoproteinemia, or hyperlipidemia, or to increase HDL. Pirenzepine is marketed overseas as an anti-ulcer drug. The following publications relate to certain experiments involving pirenzepine and diabetes.
Atiea et al. J. of Clin. Endocrinol. 69:390-395 (1989) report the administration of pirenzepine to patients suffering from insulin-dependent (Type I) diabetes (IDDM). The goal of this treatment is to suppress nocturnal growth hormone (GH) secretion, as this hormone is believed to account for the early morning rise in glucose levels seen in Type I diabetics. Both acute (single dosage) and chronic administration was studied in conjunction with overnight low dose insulin infusion. In the acute study, two doses of 100 mg of pirenzepine were given at 2200 and 2400 hours, with measurement of plasma glucose, insulin, growth hormone, glucagon, cortisol, norepinephrine and epinephrine being made. The chronic study consisted of seven days of this treatment, with measurements being taken on the seventh night.
Pirenzepine treatment under both of the Atiea dosing regimes caused a reduction in plasma growth hormone concentrations. The authors also report an increase in plasma insulin concentration after seven days of pirenzepine treatment, a result which the authors tentatively attribute to a reduction in insulin clearance from the plasma. (It should be noted that other authors, such as Bevan--see below--report a decrease in plasma insulin in similar experiments conducted using Type II diabetics.)
The Atiea study relates the timing of administration of pirenzepine with the late nocturnal growth hormone release, which pirenzepine suppresses. The attendant decrease in morning levels of blood glucose is a direct effect of growth hormone suppression and is not related to modulation of insulin sensitivity or of lipogenic sensitivity. This reference therefore does not disclose or suggest any ability of pirenzepine to modulate either insulin sensitivity or lipogenic sensitivity.
Atiea et al. make no measurements of fat stores, or plasma lipid or lipoprotein concentrations and are silent as to any effect that pirenzepine could have on these values. The entire focus is on IDDM, which is a disorder distinct from NIDDM. Moreover, there is no suggestion that the treatment with pirenzepine could or would have long-term effects following cessation of its administration.
Martina et al. J. of Clin. Endocrinol. 68:392-396 (1989) report the results of chronic (one month) administration of pirenzepine to insulin-dependent (Type I) diabetics. The pirenzepine (100 mg) was administered orally once daily at 2300 hours.
Martina et al. report suppression of nocturnal GH secretion. Measured as area under the concentration curve, GH was reduced from 1407 to 877 .mu.g/L*min. Nocturnal plasma glucose levels were reduced from a peak of about 6.5 .mu.g/L at 0300 hours to about 2 .mu.g/L at 0300 hours. This article states that early morning plasma glucose levels may have been reduced, because four of the thirteen patients studied had reduced insulin requirements, although the difference was not significant for the group as a whole.
This study relates its timing of administration of pirenzepine with the time of sleep (for reasons analogous to Atiea et al.) and makes no suggestion that this timing should be correlated with any other indicia, such as lipogenic activity. This reference does not disclose or suggest any ability of pirenzepine to interfere with lipogenic activity or with insulin sensitivity. Martina et al. make no measurements of plasma lipid or lipoprotein concentrations and are silent as to any effect that pirenzepine could have on these values.
Pietschmann et al. Acta Endocrinol. (Copenh) 117:315-319 (1988) report the effects of administering pirenzepine to patients suffering from Type I diabetes (IDDM). Two doses of pirenzepine (50 mg) were given orally in random order with a placebo at 2130, 0800, and 1200 hours. Plasma glucose, cortisol, insulin, and C-peptide were measured every three hours.
Both plasma glucose levels (10 mmol/L vs. 8 mmol/L at peak) and serum GH levels (6 .mu.g/L vs. 3 .mu.g/L at peak) were significantly lowered by the pirenzepine treatment. However, cortisol, insulin and c-peptide levels were unaffected by the treatment.
The effects of pirenzepine on blood glucose reported in the Pietschmann study are completely accounted for by the concomitant decrease in growth hormone. Furthermore, this study does not relate the timing of administration of pirenzepine with any particular time of the day, and makes no suggestion that this timing should be correlated with any other indicia, such as lipogenic activity. This reference does not disclose or suggest any ability of pirenzepine to produce long-term effects following the cessation of treatment. Pietschmann et al. make no measurements of fat stores, or plasma lipid or lipoprotein concentrations and are silent as to any effect that pirenzepine could have on these values or on insulin resistance.
Bevan et al. Clinical Endocrinol. 36:85-91 (1991) report effects of administration of pirenzepine to human subjects suffering from NIDDM. Five non-obese and five obese NIDDM patients were studied. Pirenzepine (200 mg) was given orally once, at 0800 hours, following an overnight fast. Breakfast was then given at 0900 hours, and measurements of plasma glucose and insulin were subsequently made.
Bevan et al. mention the correlation between hyperinsulinemia and coronary heart disease and suggest that pirenzepine could be used to treat obese NIDDM patients susceptible to high insulin values. However, Bevan do not measure nor report a change in fat, or in any of the other lipid metabolism parameters mentioned above. Furthermore, their experiment suggests only that pirenzepine lowers plasma glucose and insulin response after a meal. Bevan's observation of reduced insulin levels was not accompanied by a reduction of blood glucose (in fact blood glucose levels were slightly higher though the change was not significant). This means that insulin sensitivity was either unaffected (or that it may have been adversely affected if the blood glucose increases were significant).
Bevan administered pirenzepine only at 08:00 and therefore was not able to discern or to suggest any effects of the presence of pirenzepine in the blood at other times of the day.
The Bevan study relates the timing of administration of pirenzepine solely with the timing of a meal, and makes no suggestion that this timing should be correlated with any other indices, certainly not lipogenic sensitivity. This reference does not disclose or suggest any ability of pirenzepine to interfere with lipogenic sensitivity or insulin sensitivity (or even to affect basal insulin or glucose levels) or to instill a benefit that persists after cessation of therapy. Bevan et al. make no measurements of fat stores, or plasma lipid or lipoprotein concentrations and contain no data or suggestion that pirenzepine would have any effect on their values.
The results reported in Bevan et al., for NIDDM subjects can be attributed to the direct effects of pirenzepine on insulin and growth hormone production. Pirenzepine, by inhibiting cholinergic activity, acutely suppresses insulin secretion and accounts for the reduced insulin secretory response to a meal after a single dose of pirenzepine. The acute effects of pirenzepine would be to reduce growth hormone secretion and directly lower blood glucose concentration.
Pirenzepine antagonism of gastric and duodenal motility acts to slow absorption of a meal and therefore considerably blunts and delays the post-prandial rise in plasma glucose concentration, as seen in Beyan et al.
Coiro, V. et al., Gen. Endocrinol. Invest., 1986, 9:27-30 report that pirenzepine (three doses during the day of 25 mg each and a fourth 50 mg dose two hours before glucose injection) did not alter basal glucose level and did not significantly increase blood glucose level after i.v. glucose administration in normal human subjects. At the same time, insulin release was reduced. As discussed with respect to Bevan et al. above, pirenzepine by inhibiting cholinergic activity suppresses insulin response to a glucose load. There is no suggestion in Coiro that insulin sensitivity has been increased and Coiro contains no disclosure nor inference about modulation of lipid metabolism.
All of the foregoing references (other than Beyan et al.) disclosing use of pirenzepine or methylscopolamine to modulate glucose metabolism involve either normal or insulin-dependent (Type 1, IDDM) diabetic subjects. All of these references teach the use of these M1 muscarinic receptor antagonists for their direct effect alone, i.e. for their ability to suppress growth hormone or to inhibit cholinergic activity and thereby suppress insulin. There is no teaching of either a short-term or long-term modulation of insulin sensitivity or lipid metabolism.
Thomas et al., Sem. Hop. Paris 53:1857-1862 (1977) discuss the effect of bromocriptine on diabetics. Bromocriptine (7.5 to 20 mg) is given daily by mouth. No timing is reported for administration.
The results of the treatment did not indicate particular efficacy, with six patients having improvement in glucose regulation, 4 having aggravation, and 14 showing no significant change. The results were not dependent on the type of diabetes or the patient age, but appeared to the authors to be more effective in patients who had been diabetic for a shorter time and who were less affected by diabetic retinopathy.
This reference does not mention the timing of the administration of the drug and does not suggest that timing would or could be important. Further, the reference does not report any effect on lipid regulation. There is also no suggestion to combine this treatment with any other drug treatment, such as pirenzepine.
Barnett et al., Postgrad. Med. J. 56:11-14 (1980) report effects of treatment of maturity onset (Type II) diabetes with bromocriptine or metoclopramide. Bromocriptine (2.5 mg) was administered once 2 hours prior to the glucose challenge. Plasma glucose, growth hormone, prolactin and insulin were measured at 15 minute intervals both before and after the glucose administration.
Bromocriptine treatment was found to decrease plasma glucose concentration, which was taken to indicate an improvement in glucose tolerance. Plasma insulin decrease with drug administration was significant. As expected, bromocriptine decreased markedly plasma prolactin levels.
The decrease in plasma glucose levels reported with Type II patients in this study was also significant. The authors hypothesized that glucose decrease may be due to bromocriptine's ability to reduce prolactin levels in these patients without an increase in growth hormone levels.
The Barnett reference does not disclose or suggest a continuing tratment with bromocriptine, nor a long-term modulation of plasma glucose via bromocriptine administration. Furthermore, the reference does not mention the importance of determining the timing of the administration of the drug and makes no mention of the ability of bromocriptine to affect lipogenesis or to have a long-term effect. There is also no suggestion to combine this treatment with any other drug treatment, such as pirenzepine. Finally, there is no mention of effects on fat stores, or plasma lipid or lipoprotein concentrations.
Poland, R. E. et al., 1989, Biol. Psychiatry 25:403-412 disclose that scopolamine (3.0 .mu./kg and 6.0 .mu.g/kg) was administered intramuscularly at 11:00 pm to eight normal male volunteers. Scopolamine produced a significant dose-related delay in rapid eye movement latency, but did not affect nocturnal plasma cortisol concentrations.
Davidson, M. B. et al., Diabetes, 1988, 37:166-171 discloses administration of a sleeping medication alone with five milligrams methscopolamine bromide to Type I diabetic patients at 2230h resulting in marked inhibition of peak growth hormone (known to be a lipolytic and hyperglycemia-inducing agent) concentrations after sleep. Methscopolamine also caused the dawn effect (i.e. the increase in plasma glucose concentration observed in diabetics early in the morning) to decrease.
Grigoriev, A. I. et al., Aviat. & Environ. Med., 1988, 59:301-305 disclose the administration of scopolamine (0.01 mg/kg given orally 2 hours before exposure to rotation) significantly decreased the susceptibility of normal subjects to motion sickness caused by rotation in moderate susceptibility subjects. However, time course variations of hormone concentrations (ACTH, cortisol, STH and prolactin) were identical between scopolamine and placebo receiving subjects.
Mendelson, W. B. et al., J. Clin. Invest., 1978, 61:1683-1690 disclose administration of 0.5 mg methscopolamine bromide intramuscularly to normal subjects at 10:pm, 1/2 hour before bedtime. The drug dramatically reduced both overall growth hormone levels and mean peak growth hormone levels during the night but did not affect sleep patterns or insulin-induced hypoglycemia. The authors conclude that methscopolamine did not affect prolactin levels during sleep.
Curtis-Prior, P. B. et al., Experientia, 1979, 35:1430-1431 disclose that scopolamine hydrobromide did not significantly affect glycerol release from isolated fat cells (a lipolytic index) of rats in vitro nor inhibited adipose tissue cyclic AMP phosphodiesterase activity.
Ostinson, C.-G. et al., Endocrinol., 1987, 121:1705-1710 disclose that fasting decreased the binding of the muscarinic antagonist methylscopolamine to pancreatic islet cells of non-diabetic rats. However, binding of methylscopolamine to islets of rats with diabetes (that serve as an animal model for IDDM) induced by streptozotocin (STZ, which destroys .beta.-cells) was enhanced by 80% compared to binding to normal cells and that this increase was due to increased number of binding sites of the STZ islets. Insulin treatment of STZ rats lowered the binding of methylscopolamine. These results lead the authors to conclude that glycemia partisipates in the regulation of the number of muscarinic receptors expressed in pancreatic islet cells and this regulation is associated with changes in cholinergic-induced insulin secretion. These data indicate that methylscopolamine increases blood glucose concentration which would lead one to expect that methylscopolamine would exacerbate symptoms of diabetes.
Davidson, M. B. et al., Diabetes Care 1990, 13:813-814 disclose that methscopclamine bromide suppressed sleep induced growth hormone secretion and attenuated the dawn phenomenon when given at bedtime. Chronic use of 5 mg of methylscopolamine bromide was not particularly well tolerated by most patients and, according to the authors, this therapy did not "appear to be a clinically useful approach to achieving euglycemia."
Davis, B. M. et al., Psychoneuroendocrinology, 1982, 2:347-354 report that administration of methscopolamine (0.5 or 0.75 milligrams subcutaneously) decreased the elevated AVP, cortisol and prolactin levels of subjects that experience unpleasant side effects after administration of physostigmine. Methscopolamine also inhibited growth hormone secretion.
Risch, S. C. et al., Psychoneuroendocrinology, 1986, 11:221-230 report that muscarinic receptor antagonist methscopolamine inhibited the affect of physostigmine on plasma concentrations of pituitary hormones including cortisol, prolactin, adrenocorticotropic hormone (ACTH) and others.
The administration of pirenzepine or methyl scopolamine (or other muscarinic M1 receptor antagonists) optionally in combination with bromocriptine (or another dopamine agonist or other substance that reduces plasma prolactin levels) for affecting lipogenesis and ameliorating symptoms of lipid metabolism disorders and. Type II diabetes according to the present invention has not been previously disclosed. Nor has it been proposed to use such muscarinic receptor antagonists (alone or in conjunction with dopamine agonists) at predetermined times during a 24-hour period to reduce lipogenesis or lipogenic activity, or to improve glucose metabolism. Further, these uses of muscarinic and particularly M1 receptor antagonists in countering hyperlipoproteinemias by increasing the HDL fraction of lipoproteins has also not been previously disclosed, and is an aspect of the presently claimed invention. Additionally, the use of these antagonists to reduce over the long term (even after cessation of treatment) body fat stores or plasma lipid concentration (and thereby combat atherosclerosis) has not been proposed before the present invention.